Despite numerous attempts to understand the molecular mechanisms behind the development of liver cancer, it continues to pose a significant worldwide health challenge. Transcriptome sequencing, a powerful tool in molecular biology, has played a pivotal role in uncovering the intricate gene expression profiles underlying hepatocellular carcinoma (HCC). In the present study, we identified a total of 808 differentially expressed genes (DEGs), with 584 exhibiting downregulation, and 224 showing upregulation following apigetrin treatment. We utilized a combination of bioinformatics tools and platforms, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and mapping, Protein-Protein Interaction (PPI), and GEPIA. We found that DEGs were related to the apoptotic cell death process and identified hub genes, namely CASP8, RB1, and TGFBR2. These genes were further validated through both GEPIA analysis and western blot experiments. Our findings collectively demonstrate that apigetrin has the potential to modulate genes related to liver cancer and trigger molecular pathways that lead to apoptotic cell death in liver cancer cells. This study underscores the potential of apigetrin as an innovative treatment strategy for HCC, emphasizing the need for additional research to elucidate its mechanisms of action and evaluate its clinical efficacy.